About 400 million people worldwide suffer from one or other type of bladder disease. Bladders can be ravaged by cancer, birth defects, nerve damage or trauma. When conservative therapies are not effective, bladder augmentation or urinary diversions are recommended as alternative therapeutics. Apart from the shortage of available donors, the disadvantages of autografts such as formation of bladder stones, increased risk associated with allografts, induction of hyperacute rejection due to potential mismatch of xenografts and the possible transmission of zoonoses due to xenografts have obviated the need for alternative repair options. Small intestinal submucosa (SIS), a natural biodegradable matrix, has shown significant success in bladder regeneration. However, it is a natural matrix and large-scale preparations are hindered by various physicochemical properties which affect the quality and reliability of the tissue regeneration in the clinical settings. The goal of this project is to develop a synthetic matrix mimicking the characteristics of the SIS. The underlying hypothesis is that blends of synthetic and natural matrices can be optimized by altering their proportions and configurations in the matrix. We will tailor the mechanical and degradation properties using synthetic polymers while the biological response will be regulated by natural polymers such as gelatin. For this purpose, scaffolds of two distinct configurations with amorphous 50:50 poly-lactide- co-glycolide (PLGA) or semi-crystalline ploycaprolactine (PCL) will be combined with chitosan and gelatin in different proportions. However, synthetic scaffolds do not have growth factors to influence cell colonization in addition to blood vessel-like structures unlike SIS. For this purpose, we will utilize the novel nanotechnology to prepare and characterize chitosan nanoparticles containing basic fibroblast growth factor (bFGF) and Transforming growth factor (TGF)- beta on bladder regeneration in vitro and evaluate the quality of the regenerated tissue. The Specific Aims of this grant application are: Specific Aim 1. To develop synthetic matrices mimicking SIS physicochemical characteristics. Specific Aim 2. To evaluate cell colonization in synthetic scaffolds. Successful completion of this project will establish a ground work for new therapeutic strategies to improve large pieces of full-thickness bladder augmentation/reconstruction for patients who require surgical restoration of bladder function. Further, utility of controlled delivery of growth factors using nanoparticles and efficacy of combining natural matrices with synthetic matrices will pave the way for regenerating other tissues. Project Relevance statement The goal of this project is to develop a synthetic matrix mimicking the characteristics of the SIS which has shown promise in tissue regeneration. We will tailor the mechanical and degradation properties using synthetic polymers while the biological response will be regulated by natural polymers such as gelatin. We will also utilize the novel nanotechnology to prepare chitosan nanoparticles containing basic fibroblast growth factor (bFGF) and Transforming growth factor (TGF)- [unreadable] and characterize their in vitro release kinetics. Successful completion of this project will establish a ground work for new therapeutic strategies to improve large pieces of full-thickness bladder augmentation/reconstruction for patients who require surgical restoration of bladder function.